We have begun to examine the neurodegeneration that occurs in a genetically modified mouse that was developed by our collaborators at the Karolinska Institute in Sweden. We have now established a successful breeding colony of these mice at our institute, and we have made them available to our local collaborators. These mice possess a mutation in the mitochondrial gene known as mitochondrial transcription factor A (tFam). This gene regulates mitochondrial DNA transcription in all cells, and is necessary for continued oxidative phosphorylation. However, by targeting this mutation to dopamine neurons using the promoter that drives dopamine transporter expression, only these neurons are affected by the mutation. Our present work shows that the DA neurons degenerate slowly over a 30 week period, and that these """"""""MitoPark"""""""" mice display many hallmarks of Parkinsons disease in humans. This includes sensitivity to pharmacological treatments, such as L-Dopa therapy, and the loss of this therapeutic benefit as the neurodegeneration progresses. Our studies have also shown that expression of glial cell line-derived neurotrophic factor (GDNF) through adeno-associated virus (AAV) can spare these dopamine neurons, and protect against either neurotoxin or genetically induced parkinsonism in mice. In addition, in pilot studies conducted with the dopamine neurotoxin MPTP, we have found that the loss of dopamine causes profound changes in the physiological properties of the striatum that were also prevented by AAV-mediated gene expression of GDNF. We will now begin to test this form of gene therapy in the tFam genetic model of Parkinsons disease, and attempt to reverse the neurodegeneration at various time points during the disease progression. Our most recent work with the MitoPark mice reveals an interesting change in DA neuron physiology at a time during development at which the animals are behaviorally asymptomatic. We find a dramatic reduction in the presence of a membrane current known as """"""""Ih"""""""" in the DA neurons located in the substantia nigra, This current is normally involved in re-setting the neuronal membrane potential near action potential threshold following a large inhibition. Therefore, Ih may be involved in maintaining normal pacemaking activity in DA neurons. We are currently assessing the relevance of this change in Ih density in MitoPark mice, and theorize that a loss of Ih may represent one of the early consequences of mitochondrial impairment in DA neurons degenerating in Parkinson's disease. Our current studies show that the mRNAs encoding Ih are not altered in MitoPark mice suggesting that the down-regulation of these ion channels is post-translational. In the most recent reporting period we have found that DA neurons in MitoPark mice are impaired compared to control mice, and that this impairment leads to a reduction in the available pool of DA that is releasable. The most surprising aspect of these studies is that the observed impairment in DA neuron function occurs at an age where parkinsonian symptoms are absent in these mice. Thus, we believe that this model may permit for the first time the ability to track changes in the nigrostriatal DA system over time, which should lead to promising targets for therapeutic intervention. A further developmental characterization of the dopamine neurons in the substantia nigra of these mice is currently underway to determine whether there is a progression in ion channel dysfunction as the animals begin to display more severe parkinsonian behavioral symptoms. In addition, a detailed anatomical analysis is underway to determine whether the ion channel changes we have observed are related to changes in neuronal morphology, and the loss of synaptic function
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